Background and aims    
Growing evidence suggest a critical role of distinct gut microbially produced metabolites in the development of cardiometabolic and -vascular diseases. The amino-acid derived metabolite imidazole propionate (ImP) is increased in patients with type II diabetes. However, its impact on endothelial cell physiology and vascular disease has not been examined, so far. Here, we assessed the effects of ImP on endothelial cell functions in cultured primary human aortic endothelial cells (HAECs) and on vascular regeneration in a carotid injury mouse model.

Methods and results       
Cell migration and angiogenic ability of HAECs were examined upon treatment with ImP at different concentrations (10 nM and 100 nM) using wound scratch or matrigel tube formation assays. ImP significantly reduced endothelial cell migration and the formation of tube-like structures on extracellular matrix compared to control treatment. To identify potential underlying mechanisms of ImP mediated effects on endothelial cells, next-generation sequencing, western blotting and immunostaining were performed. Transcriptomic profiling of HAECs revealed altered regulation of a number of genes involved in angiogenesis in ImP treated cells. In particular, decreased PI3K/Akt signaling under pre-treatment of ImP followed by insulin receptor stimulation with IGF-1 was found. Vascular regeneration in vivo was analyzed using a carotid artery injury model (CI) in C57BL/6N mice treated with ImP (400 µg) or vehicle for three weeks via drinking water. After treatment, CI was induced to the carotid artery using a bipolar microforceps. Re-endothelialization was determined by Evans blue staining 3 days post-CI. Our results showed, that treatment with ImP significantly impaired wound healing as compared to control animals.

Conclusion
Imidazole propionate exerts anti-angiogenic functions in the endothelium and impairs endothelial repair after injury by disturbing PI3K/Akt signaling. Our findings may contribute to the development of novel gut microbiota-related strategies targeting intestinal production of ImP to prevent or treat cardiovascular diseases.